The current 'epidemic'of obesity in the United States has been ascribed to environmental changes that have occurred over the past two decades. Prominent in this is the ready economic availability of highly palatable, high caloric density foods. Although numerous studies have focused on hormones such as insulin and leptin, and neurotransmitters, which act at the medial hypothalamus to regulate calorie intake, little attention has focused on the potential regulation of central nervous system (CNS) circuitry which mediates the rewarding or motivating aspects of food. This circuitry includes the midbrain dopamine neurons (DA) as well as other forebrain areas with which the medial hypothalamus has extensive direct and indirect connections. Our lab has evidence that the candidate adiposity signals insulin and leptin decrease performance in behavioral tasks that assess food reward and that require DA signaling. We hypothesize that the midbrain DA neurons whose cell bodies are in the ventral tegmental area (VTA) serve as a direct target for insulin and leptin. In this proposal we will test this hypothesis in rats by studying the effects of insulin or leptin infused directly into the VTA on behavioral procedures that evaluate different aspects of food reward/motivation: a free-feeding ingestive task, the conditioned place preference, and self-administration. We will compare sweet vs. fat food reward in these tasks, to evaluate macronutrient specificity. We will infuse insulin receptor antisense oligonucleotides directly into the VTA to determine the role of endogenous insulin signaling in modulation of food reward behavior. Because VTA DA neurons express insulin and leptin receptors, we will measure insulin- and leptin-stimulation of the PI3 kinase pathway as an index of direct VTA activation at the cellular level. Comparable studies will be carried out in rats fed a defined high fat diet snack in addition to chow, a model of CNS insulin resistance that we have recently developed. We will use this model to test whether the behavioral and cellular actions of insulin and/or leptin at the VTA are blunted by high fat diet ingestion, i.e., a model of VTA insulin or leptin resistance. Together these studies will evaluate the potential regulation of reward circuitry and function in the CNS by adiposity signals. Findings from these studies will contribute to the long-term goal of learning whether altered food reward value contributes to the (relative) overeating which occurs in association with the availability of highly palatable foods, independent of caloric need.